Pyroptosis is a type of inflammatory programmed cell death in the body that is mediated by the cleavage of gasdermin proteins. When gasdermin (GSDM) is cleaved, the N-terminal (NT) domain is freed from the auto-inhibitory C-terminal domain and becomes activated. This activated NT fragment assembles to form membrane pores, triggering pyroptotic cell death and releasing cellular contents into the extracellular space to promote inflammation.

The cleavage of GSDMD is known to be catalyzed by a protease named caspase 4. Caspase 4, as an intracellular microbe sensor, recognizes intracellular LPS and mediates the cleavage of GSDMD to trigger pyroptosis. Additionally, Caspase 4 can cleave and activate IL-18.  However, no other Caspase 4 substrates have been reported so far. The aim of this project is to investigate additional targets of Caspase 4 within the interleukin-1 (IL-1) family. The IL-1 family, comprised of eleven cytokines, is closely associated with the body’s immunity and can employ both pro- or anti-inflammatory mechanisms when activated. Some of these cytokines, such as IL-1β and IL-18, are known to be secreted through the membrane gasdermin pores during pyroptosis. However, it is not yet known whether other members of the IL-1 family could also be cleaved and released during pyroptosis.

This project will utilize molecular and cellular biology techniques to study CASP4 cleavage of IL-1 family proteins and investigate their corresponding physiological roles. Identifying these substrates will provide more insight into the details of pyroptosis and caspase-related molecular pathways, which play important roles in inflammation and are involved in infectious diseases and cancer.

CaNCURE Research Presentation: https://youtu.be/U04Okin7Oxs